Statins improve cardiovascular morbidity and mortality presumably secondary to their inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase leading to decreases in low-density lipoprotein cholesterol (LDL-C). However, some of statins? CV benefits appear to be independent of decreases in LDL-C. These pleiotropic benefits are similar to those observed with mineralocorticoid receptor (MR) blockade, leading us to hypothesize: statin therapy reduces aldosterone (ALDO) and this reduction contributes to some of statins? cardiovascular benefits. Thus, this proposal focuses on statins? effects on aldosterone regulation. This hypothesis is supported by our strong preliminary data. In two observational studies, statin use was associated with a ~30% decrease in ALDO levels at baseline and after angiotensin II (AngII) or upright posture as well as a decrease in systolic blood pressure and salt-sensitivity of blood pressure. Further, lipophilic statins were more potent than hydrophilic statins. In our preliminary studies to assess mechanism, we showed that addition of a statin to incubates of acutely isolated rat zona glomerulosa cells decreased baseline and AngII- stimulated ALDO production, without affecting corticosterone. Simvastatin (a lipophilic statin) reduced ALDO more than pravastatin (a hydrophilic statin). Thus, our overall hypothesis is that ALDO levels are reduced by statins, particularly lipophilic statins, leading to decreased cardiovascular injury and that the mechanism for the ALDO reduction involves inhibition by statins of the last step in aldosterone biosynthesis. To address this hypothesis we will perform the following specific aims: Aim 1. To perform a prospective, randomized, placebo-controlled trial in humans testing the hypothesis that statins reduce ALDO levels, with a lipophilic statin having greater efficacy than a hydrophilic statin. Aim 2. To test the hypothesis, in rats, that a key mechanism underlying the adrenal effects of statins is the inhibition of ALDO synthase (CYP11B2) through changes in enzyme activity and/or levels. Aim 3. To test the hypothesis, in a rat model of ALDO-dependent cardiovascular injury, that a lipophilic statin will reduce cardiac damage. Currently, the beneficial effects of statins are generally assumed to be secondary to their LDL-C lowering effects. If our hypothesis proves to be true, it will substantially shift the focus of how to enhance statins? beneficial effects from a singular approach on reducing lipid levels to a dual approach of lowering ALDO and LDL-C. These results could provide an answer as to why some statins produce a beneficial cardiovascular effect when LDL-C levels are already normal or low, and why some statins that reduce LDL-C levels less than other statins have greater protective effects. Finally, for new drug development, our results will shift the focus from creating molecules that are simply better at lowering LDL-C to ones that are better optimized to lower both LDL-C and ALDO.